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Title: The brain microenvironment and its role in oligodendrocyte progenitor cell ageing
Author: Molotova, Alisa
ISNI:       0000 0004 8507 8068
Awarding Body: University of Cambridge
Current Institution: University of Cambridge
Date of Award: 2020
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The overall aim of my thesis was to study age-related changes in molecular interplay between the brain extracellular matrix (ECM), oligodendrocyte progenitor cells (OPCs) and astrocytes. During ageing the resident brain progenitors undergo cellular arrest causing a diminished regenerative response. Increasing research evidence supports the notion that the ageing brain ECM not only provides structural support, but also directs progenitor cell fate and function. Concurrently, the ECM biochemical and biophysical properties modulate the ageing OPC phenotype. In my PhD thesis, I aimed to i) characterise biophysical and biochemical changes of the ageing brain tissue, ii) examine how these changes influence the resident OPC regenerative capacity and iii) investigate how brain tissue properties influence ECM and chemokine synthesis in astrocytes. I have demonstrated that gradual brain stiffening with age, not only has detrimental effects on brain progenitor function, but also promotes astrocyte reactivity, inflammatory response and astrogliosis. In addition, I demonstrated that on stiff substrates astrocytes phenocopy aged cells on both transcriptional and functional level. Consequently, astrocytes on stiff substrates secreted ECM that significantly inhibited OPC proliferation and differentiation. In addition, using nanoindentation I showed that brain tissue hydraulic permeability decreases with age, while its white and grey matter become stiffer in a region-specific manner. Furthermore, I demonstrated that the associated changes are not only biophysical but also biochemical in their nature using mass spectroscopy and Fourier-transform infrared spectroscopy. Specifically, I observed qualitative and quantitative changes in protein and glycan composition, where the ageing glycans also proved to be inhibitory to OPC regenerative function, as determined in cell culture assays. My findings imply that the brain ECM biochemical and mechanical homeostasis is crucial for OPC maintenance and maturation. This research into how ECM changes with age and how these alterations contribute to the ageing of brain progenitor cells will provide attractive new therapeutic targets to tackle ageing disorders.
Supervisor: Franklin, Robin J. M. ; Chalut, Kevin Sponsor: Wellcome Trust
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
Keywords: oligeodendrocyte ; OPC ; microenvironment ; brain stiffness ; astrocytes ; ageing ; glycans